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Programmed cell death, or apoptosis, is a multifactorial event that can be triggered by an array of pathophysiological conditions. The cellular mechanisms by which myocardial apoptosis occurs in response to stress-induced and/or neurocrine-mediated signaling pathways are quite complex. These have been the focus of numerous investigations over the past decade (1). Important conditions associated with cardiac myocyte apoptosis include ischemia-reperfusion (2), heart failure (3), and sepsis (4).

Exposure of heart to lipopolysaccharide (LPS), as happens in patients with sepsis, activates a myriad of cellular events. The adverse effect of LPS on cardiac function has been known for many years. Yang et al. (5) reported that left ventricular function was reduced after administration of LPS, and postulated that the activation of nitric oxide synthase (iNOS) and release of large amounts of nitric oxide (NO) in response to LPS was responsible for diminished cardiac pump function. Along the same line of thought, Li et al. (4) showed that activation of iNOS and subsequent cyclic guanosine monophosphate (cGMP) accumulation, and activation of local renin-angiotensin system led to myocyte injury resulting in cardiac dysfunction. Yasuda and Lew (6) reported that exposure of cardiac myocytes to LPS decreased cell shortening with no change in calcium transients, indicating decreased myofilament responsiveness to calcium. They demonstrated that these effects were mediated in large part via NO-cGMP–mediated mechanisms.

In this issue of the Journal, Suzuki et al. (7) describe a novel cellular mechanism by which LPS induces apoptosis in rat cardiac myocytes. After exposure to LPS, these investigators report that calcineurin, a central regulator of calcium-mediated signals, is activated in cardiac myocytes and leads to apoptosis. Calcineurin, also known as protein phosphatase 2B, is a ubiquitous calcium-sensitive protein phosphatase composed of a catalytic and a regulatory subunit. Calcineurin is a major participant in the development, cellular regulation of calcium homeostasis, and intracellular trafficking in most mammalian tissues (8). The role of the calcineurin as a mediator of pathological hypertrophy has been largely established (9). In the myocardium, calcineurin is a central pro-hypertrophic signaling molecule (10). The catalytic beta-isoform of calcineurin is up-regulated in the cardiac myocytes in response to hypertrophic stimulus (11). Various genetic approaches have supported the importance of the calcineurin signaling pathway in the regulation of cardiac growth (12). De Windt et al. (13) have also shown that calcineurin-mediated hypertrophy protects cardiac myocytes from apoptosis, both in vivo and in vitro.

While it is possible and likely that the failing heart develops apoptosis in late stages, the description of apoptosis due to calcineurin activation soon after exposure of cardiomyocytes to LPS in vitro by Suzuki et al. (7) remains intriguing. Importantly, this group previously showed that angiotensin II, a product of renin-angiotensin system activation increased apoptosis in cardiac myocytes, and the effect of angiotensin II was blocked by losartan. Angiotensin II is synthesized by cardiac myocytes and can lead to apoptosis and hypertrophy of cardiomyocytes (14).

It is quite possible that cell growth and apoptosis go hand in hand, and the preponderance of hypertrophy or apoptosis depends upon the stimulus, duration of exposure to the stimulus, intensity (dose) of the stimulus, and environment in which cardiac myocytes are going through cell cycle.

Suzuki et al. (7) suggest that calcineurin is released after release of angiotensin II and its activation. In their studies, calcineurin-mediated apoptosis was not accentuated by angiotensin II, implying that angiotensin II acts proximal to calcineurin pathway.

They show a dose-dependent increase in calcineurin activity in response to LPS. Since the number of apoptotic cells increased by ∼40% simultaneously, and cyclosporin A prevented the pro-apoptotic affects of LPS, it is likely that calcineurin had a potent effect on cell cycle. The link between LPS, calcineurin, and apoptosis would have been stronger if they had provided data on LPS-mediated increase in calcineurin messenger ribonucleic acid (mRNA) and protein. While it is possible that calcineurin activity increases without a change in mRNA and protein after exposure of cardiac myocytes to LPS, the pathways leading to calcineurin expression and activation need to be better defined.

Although cyclosporin A alters the T-cell receptor signal transduction pathway via formation of a complex with cyclophilin that inhibits calcineurin, it has also been shown to inhibit NO synthesis induced by LPS and cytokines (15). In this context, it may be difficult to determine if the effects of cyclosporin A treatment on apoptosis are distinct from a direct action on calcineurin or if other factors also contribute to this inhibition.

While the authors’ work has some novelty, further work needs to be done before the paradigm of the effect of LPS on cardiac myocyte apoptosis being mediated by calcineurin activation can be fully accepted. As the authors point out, these findings do not prove that calcineurin activation is required for LPS-induced apoptosis. Moreover, studies are needed to elucidate the downstream signaling pathways that are triggered after LPS-induced calcineurin activation.

Calcineurin activation in response to LPS described in this issue of the Journalexpands the paradigm of organ preservation during injury. It remains to be determined whether calcineurin temporally regulates only the pathological development of hypertrophy, or whether it is also involved in the cellular mechanisms leading to cell death.

Apoptosis is an important mechanism of cell survival, replication, and death. The mechanisms involved in its genesis are far from clear. While a number of investigators have shown that apoptosis can be prevented, to the best of our knowledge no one has shown that program of cell death while in motion can be undone.

Footnotes

↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.

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